Antigens expressed by tumor cells are an increasingly popular target for the development of immunotherapeutics in the treatment of cancer. Vaccines against such antigens have been developed in hopes of directing an immune response against tumors causing attenuation and regression of tumor growth. However, tumor and cancer vaccines have had limited success due to, among other things, immunosuppressive mechanisms associated with the tumor itself and its associated microenvironment. These mechanisms include the secretion of TGF-β or IL-10 leading to Th2 polarization (Frumento et al. 2002; De Vita et al. 2000; Berghella et al. 1997). Even when favorable vaccination conditions promote robust tumor-specific immunity, increases in intratumoral regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) within the tumor microenvironment attenuate the anti-tumor immune response (Norian et al. 2009; Polak et al. 2009; Gajewski et al. 2006; Whiteside 2008). Therefore, recruitment of large numbers of tumor-recognizing T cells by a cancer vaccine is not, on its own, sufficient to mediate tumor regression unless the tumor microenvironment is inhibited from dampening T cell function.
Tregs and other immune cells present within the tumor microenvironment are thought to protect tumors from potentially effective immune responses through several immunomodulatory mechanisms (Rodriguez et al. 2003). These mechanisms contribute to tumor-derived immune suppression. For example, activated Tregs may stimulate myeloid-derived suppressor cells to produce indoleamine 2,3-dioxygenase 1 and 2 (IDO1 and IDO2), Arginase 1 and inducible nitric oxide synthase (iNOS), each of which play a role in suppressing effector T cell function, stimulating T cell apoptosis and activating Treg cells to provoke further suppressor functions (see FIGS. 1A-B, 2, and 3). (Sakaguchi et al. 2009, Hwu et al. 2000; Uyttenhove et al. 2003) In addition, signal transducer of transcription 3 (STAT3) has been recognized as an oncogenic transcription factor in myeloid or tumor cells that, when activated, inhibits production of immunostimulatory molecules and promotes expression of immunosuppressive molecules (see FIG. 4) (Kortylewski & Pardoll 2005; Yu et al. 2007; Wang et al. 2004).
Because the immunosuppressive mechanisms associated with the tumor and the tumor microenvironment allow the tumor to evade an immune response generated by a cancer or tumor vaccine, there is a need for cancer treatments that interfere with these mechanisms to increase the efficacy of such vaccines.